Phenytoin--valproic acid interaction in rhesus monkey.
The interaction between phenytoin (PHT) and valproic acid (VPA) was investigated in the rhesus monkey. PHT was given by multiple IV bolus to reach a steady state and then continued while two successive VPA infusions were added. Plasma was assayed for total VPA and PHT as well as free PHT. The addition of VPA produced no change in total PHT levels, a 50% increase in PHT free fraction (increase in free PHT levels), and a decrease in PHT overall elimination rate constant. The increase in free fraction was also documented in a separate in vitro study. The increase in free PHT levels suggested that VPA decreased PHT intrinsic metabolic clearance. This interaction may thus involve a dual mechanism-namely protein binding displacement of PHT and inhibition of PHT metabolism. This mechanism is compatible with other studies showing that VPA is an inhibitor of drug metabolism.
D000818:Animals; D004347:Drug Interactions; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010672:Phenytoin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D014635:Valproic Acid / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D014635:Valproic Acid; D010672:Phenytoin